Tandem Diels-Alder

Alkynes substituted with one or two trifluoromethyl groups are also highly reactive dienophiles [9] Indeed, hexafluoro-2-butyne is used increasingly as a definitive acetylenic dienophile in "difficult Diels-Alder reactions. It was used, for example, to prepare novel inside-outside bicycloalkanes via its reaction with cir,trnns -l,3-undecadiene [74] (equation 67) and to do a tandem Diels-Alder reaction with a l,l-bis(pyrrole)methane [75] (equation 68) Indeed, its reactions with pyrrole derivatives and furan have been used in the syntheses of 3,4-bis(tri-fluoromethyl)pyrrole [76, 77] (equation 69) and ],4-bis(trifluoromethyl)benzene-2,3-oxide [78] (equation 70), respectively. 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

A tandem Diels-Alder reaction (the term refers to two operating units that are distinct but working at the same time) would indicate a process involving two distinct Diels-Alder reactions working at the same time (Equation 1.29) [6], and a cascade Diels-Alder reaction would refer to a transformation involving at least two Diels-Alder reactions occurring in sequence, without any reference to the fact that the subsequent reaction is the consequence of the functionality generated in the previous reaction (Equation 1.30) [61]. 

Winkler J. D. Tandem Diels-Alder Cycloadditions in Organic Synthesis Chem. Rev. (Washington, D. C.) 1996 96 167-176... 

Isochromones lose carbon dioxide on heating via retro-Diels-Alder pathway to result in o-quinodimethanes (equation 81)1241,129. An isochromone route to podophyllotoxin derivative has been described (equation 82)130. Diels-Alder adducts of a-pyrone readily extrude carbon dioxide on thermal activation to furnish cyclohexadienes, which are useful substrates in tandem Diels-Alder reactions (equation 83)131. 

The tandem Diels-Alder reaction of bisdiene 129 and bisdienophile 128 led to the production of a highly complex molecule as a single stereoisomer. Three new rings and six new stereogenic centers were created during the process [108]. 

For a tandem Diels-Alder/fragmentation approach to the eleutherobin aglycone, Winkler et al. used Marshall s protocol in an early step of the synthesis. The building block 95 was prepared in that way (Scheme 15.24) [56]. 

Scheme 19.17 A tandem Diels-Alder approach to eleutherobin.

The domino cycloaddition-iV-acyliminium ion cyclization cascade has been extensively reviewed. Tandem reactions combining Diels-Alder reactions and sigma-tropic rearrangement reactions in organic synthesis have been extensively reviewed. The tandem Diels-Alder reaction between acetylenedicarboxaldehyde and N,N -dipyrrolylmethane has been extensively studied at the RHT/3-21G and RHF/6-31G levels.The molecular mechanism of the domino Diels-Alder reaction between hexafluorobut-2-yne and A,A -dipyrrolylmethane has been studied using density functional theory. 

A review of Claisen rearrangements in aqueous solution has appeared. The synthesis of natural products utilizing tandem Diels-Alder additions with sigmatropic rearrangement processes has been reviewed, and a brief review of the regioselective synthesis of coumarins, quinolones and thiocoumarins with 3,4-fused pyran or furan ring systems by the Claisen rearrangement has been presented. ... 

For the first time, application of sequential Diels-Alder reactions to an in situ-generated 2,3-dimethylenepyrrole was shown with various dienophiles 548 to afford 2,3,6,7-tetrasubstituted carbazoles (549). This novel tandem Diels-Alder reaction leads to carbazole derivatives in two steps, starting from pyrrole 547 and 2 equivalents of a dienophile, and is followed by 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) oxidation of the intermediate octahydrocarbazole. Mechanistically, the formation of the intermediate octahydrocarbazole appears to involve two sequential [4+2] cycloadditions between the exocyclic diene generated by the thermal elimination of acetic acid and a dienophile (529) (Scheme 5.17). 

Tandem Diels-Alder-Nitronic Ester Cyclization Reactions 1122... 

Nitrones can be generated by Michael reaction of oximes with appropriate conjugated substrates.25 If a generated nitrone has a built-in dipolarophile, cyclization can ensue (Scheme 15). There are three synthetic variations on this theme.25a,b First, the oxime may contain the dipolarophile as in (56). Reaction of (56) with phenyl vinyl sulfone provided a quantitative yield of the tandem product as one stereoisomer. Alternatively, die dipolarophile can reside in the Michael substrate as in (57). Reaction of (57) with cyclohexanone oxime produced two isoxazolidines from competitive cyclization of the intermediate nitrone through six- and seven-membered carbocyclic transition states. It is also possible to carry out an intramolecular Michael addition followed by an intramolecular nitrone cyclization as in thermolysis of (58) to produce a tricyclic isoxazolidine. Very recently several examples of a tandem Diels-Alder, Michael addition, nitrone cyclization sequence have been reported.250... 

J. D. Winkler, Tandem Diels-Alder cycloadditions in organic synthesis, Chem. Rev. 1996, 96,... 

Several syntheses of pyridazinopyridazines via Diels-Alder reactions of 4-phenyl-1,2,4-triazole-3,5-dione (PTAD) (27) with functionalized dienes have been described. One example is the reaction of the diene (26) with PTAD (27) to afford the tandem Diels-Alder adduct (30) (Scheme 5) <85JCS(P1)71>. 

Tetrasubstituted-l,2,3,4,5,6,7,8-octahydrocarbazoles 1137 were synthesized in 46-90% yields by a novel tandem Diels-Alder reaction in one step from A -benzyl-2,5-dimethyl-3,4-bisacetoxymethylpyrrole 1136 and dienophiles such as maleic anhydride, maleimide, ethyl maleate, fumaronitrile, and ethyl acrylate (Scheme 222) <20000L73>. The 2,3,6,7-tetrasubstituted carbazoles 1138 were then synthesized in 29-87% yields from compound 1137 by oxidation with DDQ. 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

Independently, 2,3-bis[(trimethylsilyl)methyl)-1,3-butadiene (193) was shown to be a similar conjunctive reagent for tandem Diels-Alder reactions (Scheme 46). In this case the initial cycloadducts were subjected to an oxidative bis-desilylation with NBS and the resulting 1,2-dimethylenecyclohexanes were directly submitted to the second Diels-Alder step, as demonstrated by the reaction sequence (193) (194) -> (195). 

Cyclopentadienone equivalents, such as 4-acetoxy-2-cyclopenten-l-one, below, may serve as conjunctive reagents for tandem Diels-Alder reactions providing polycyclic adducts." ... 

In the laboratory of J.D. Winkler, the synthesis of the carbon framework of the eleutherobin aglycon was developed using a tandem Diels-Alder reaction and a Grob fragmentation as key steps.The tricyclic fragmentation precursor was subjected to potassium carbonate in DMF at 75 °C to afford the fragmentation product in 68% yield via a dianion intermediate that underwent a spontaneous hemiketalization. 

Domingo, L. R., Amo, M., Andres, J. The tandem Diels-Alder reaction of dimethyl acetylenedicarboxylate to bicyclopentadiene. A theoretical study of the molecular mechanisms. Tetrahedron Lett. 1996, 37, 7573-7576. 

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